New reports of Tau mutations associated with frontotemporal dementia (FTDP-17) suggest that mutated tau proteins may predispose the formation of NFT pathology. To test this the investigators propose to make a transgenic mouse that only expresses human mutated tau proteins. Based on the success in Phase I of creating a Tau knockout mouse, in Phase II it is proposed to make transgenic mice with each of four different human Tau mutations and mate them to the Tau knockout mice so that the offspring only express the mutated tau proteins. The investigators propose to evaluate all mice, stressed in various ways, for hyperphosphorylation of tau protein, somatodendritic relocalization of tau proteins, paired helical filament and neurofibrillary tangle pathology. PROPOSED COMMERCIAL APPLICATION: The commercial application of this research will be to develop a testing machine consisting of a transgenic mouse that develops characteristics of Alzheimers dementia and/or fronto-temporal dementia. Drugs that inhibit, stop or reverse tau-associated problems could then be tested in such a mouse.